Chronic kidney disease (CKD) is a public health epidemic that exacts an enormous financial toll on the health care system and a devastating health burden on affected patients by markedly increasing their risk of end- stage renal disease (ESRD), cardiovascular disease and premature death. Novel therapeutic strategies are desperately needed to prevent complications of established CKD, and novel diagnostic strategies are needed to support the primary prevention of CKD itself in at-risk individuals. During the first period of support under this award, we reported in the Chronic Renal Insufficiency Cohort (CRIC) Study that an elevated level of the phosphate regulating hormone, fibroblast growth factor 23 (FGF23), may be the earliest detectable abnormality of disordered mineral metabolism in CKD. We further demonstrated that elevated FGF23 is an independent risk factor for ESRD in patients suffering from CKD stages 2-3, and a potent risk factor for mortality across the spectrum of CKD: from stages 2-4 to incident hemodialysis patients and even kidney transplant recipients. Although these data established elevated FGF23 as a powerful biomarker of adverse clinical outcomes in CKD, we recently reported that elevated FGF23 is likely a mechanism of disease that contributes directly to the pathogenesis of left ventricular hypertrophy, which is a common manifestation of cardiovascular disease in CKD and a leading risk factor for major cardiovascular events and death. In this renewal application, we will expand our productive, multidisciplinary program of FGF23 research into critical new areas. In Aim 1, we will extend our ongoing work in CRIC by performing the first longitudinal study with annual repeated measures of FGF23 and mineral metabolites that will allow us to define the evolution of disordered mineral metabolism over time in CKD and its association with clinical outcomes. In Aim 2, we will capitalize on CRIC's completed genome-wide association study and its rich phenotype data to perform efficient genetic discovery studies that investigate the genetic basis underlying known racial differences in mineral metabolism. We anticipate these studies will suggest novel therapeutic targets for the future. In Aim 3, we will test whether an elevated FGF23 is an independent risk factor for incident CKD in an ancillary study to the ACCORD Trial of type 2 diabetes. If elevated FGF23 is an independent risk factor for incident CKD, it could serve as a novel diagnostic to support primary prevention of CKD. Preliminary data support our hypotheses, and our research team has the requisite expertise in FGF23, observational cohorts and population genetics to successfully complete these Aims. In addition, this project will continue to be a fertile training ground for nephrology trainees, including several recipients of K23 awards and a Minority Supplement mentored by the PI. Ultimately, the innovative studies we propose will provide insight that will help us realize our long-term goal: to develop novel therapeutic and diagnostic strategies to improve the dismal clinical outcomes experienced by patients with CKD. PUBLIC HEALTH RELEVANCE: An elevated level of the phosphate regulating hormone, fibroblast growth factor 23 (FGF23), is an independent risk factor for end-stage renal disease and mortality in patients suffering from chronic kidney disease (CKD). We will conduct the first longitudinal study with annual repeated measures of FGF23 and mineral metabolites~ we will test whether an elevated FGF23 is an independent risk factor for incident CKD~ and we will perform genetic discovery studies to investigate the genetic basis underlying known racial differences in mineral metabolism. Our long-term goal is to develop novel therapeutic and diagnostic strategies to improve the dismal clinical outcomes experienced by patients with CKD.